We have measured regional cerebral blood flow (rCBF) with oxygen-15 and positron emission tomography (PET) in patients with schizophrenia during performance of a battery of frontal lobe tasks putatively involving working memory and abstract reasoning as well as during performance of matched sensorimotor control tasks for each frontal lobe task. In monozygotic twins discordant for schizophrenia, an area of the left inferior frontal gyrus corresponding to Brodmann's Areas 9 and 46, which is the are most consistently activated by the WCS in normal subjects, was lower in the affected compared with the unaffected twin in every pair during a frontal lobe-specific task, but not during other conditions. A different prefrontal area in the left middle frontal gyrus (area 10) also invariably discriminated between cotwins, but only during a different task. The only other area that correctly discriminated between cotwins in every case was the left hippocampus, which was more active in each of the ill cotwins during the WCS, but not during any other task. One of the most intriguing findings in this study is an inverse correlation between the intercotwin differences in left inferior frontal and left hippocampal activity during the WCS. This result suggests that abnormal limbic-prefrontal circuitry may underly the cognitive deficits common in schizophrenia. The effects of pharmacological interventions are also being explored.